KCNH2 Variant K595N

Summary of observed carriers, functional annotations, and structural context for KCNH2 K595N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

28%

90% CI: 18.3% – 63.0%

4/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

K595N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 0%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.442 0.417 0 0.673 76

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Japan Cohort 2020 2 0 2
Literature, cohort, and gnomAD – 2 0 2 –
Variant features alone – 10 8 2 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15Å window.

Previously observed variants near K595N.
Neighbour residue Distance (Å) Observed variants
595 0 K595E, K595N, K595N,
594 3
604 5 G604S, G604C, G604D,
605 5 P605L,
593 5 I593V, I593K, I593T, I593R, I593X,
596 5 P596T, P596S, P596R, P596L,
590 6 G590D, G590V,
606 7 S606Del, S606P, S606F,
589 8 L589P,
603 8 G603D,
597 8 Y597H, Y597C,
591 8 D591N, D591H,
592 9 Q592X,
609 10 D609N, D609G,
610 10
586 11 L586M,
583 11 I583V,
587 11
607 11
588 12 N588D, N588K, N588K,
635 12 N635I,
633 12 N633D, N633S, N633I,
634 12 T634P, T634A, T634S, T634S, T634I,
608 13
613 13 T613A, T613L, T613K, T613M,
585 14 W585C, W585C,
584 14 G584S, G584R, G584C,
577 14
612 14 V612L, V612L, V612A,
638 15 K638E, K638D, K638Del, K638R